This invention relates to a remedy for intestinal infectious diseases, comprising as major constituent IgA-containing .gamma.-globulin. More particularly, it pertains to an oral remedy for intestinal infectious diseases, comprising an enteric-coated .gamma.-globulin containing a high concentration of IgA (hereinafter referred to as IgA-rich .gamma.-G) derived from human serum or plasma, and to a process for preparing said remedy.
Since the time when plasma fractionation began to be carried out commercially, .gamma.-globulin has been in frequent use as an important drug along with albumin and now become indispensable as prophylactic and therapeutic purposes. However, it is administered exclusively by injection in preventing and treating measles, post-transfusion hepatitis, and various other infectious diseases.
The present inventors made an attempt to administer orally the .gamma.-globulin which, heretofore, had been used in the limited way by injection, and, as the result, found that .gamma.-globulin is surprisingly effective in preventing and treating intestinal infectious diseases when administered in the form of enteric preparation. This invention has been accomplished based on this finding and an object of the invention is to provide a preparation of .gamma.-globulin which is suitable for the new uses.
After the human serum proteins had been revealed electrophoretically as albumin, .gamma.-globulin, .gamma.-globulin, and .gamma.-globulin, it has been made clear that the immune antibody is present mainly in the .gamma.-globulin and thus fractionated .gamma.-globulin has become a useful and indispensable preparation for injection in prophylaxis and therapy. With the progress of research works, the immune antibody was found to be present also in .gamma.-globulin fraction; the .gamma.-globulin, which was previously considered to be the immune antibody, together with a part of .beta.-globulin fraction was further classified into five major constituents of IgG, IgA, IgM, IgD, and IgE, each of which has its own physiological characteristics. Of these, IgA was found to be produced not only in the blood serum but also in secretory organs such as mammary gland, digestive organs, respiratory organs, etc., and is now believed to be present in the epithelial cells of mucous membrane.
The IgA found in the secretory organs is in the form of dimer consisting of two molecules of IgA, which are bridged with one molecule of secretory component (SC), is very stable against proteases and acidic condition, and is called secretory IgA (hereinafter referred to as S-IgA) as distinguished from the serum IgA (hereinafter referred to simply as IgA). Contrary to other immune globulins, IgA present in the form of S-IgA in the epithelial cells of mucous membrane attacks bacteria and viruses intruded thereinto, thus playing an important role in local immunity.
The breast milk contains S-IgA in high concentration (300 mg/dl on average in colostrum and 50 mg/dl on average in mature milk) and immunologically protects the infant who is incapable of internally producing a sufficient quantity of the immune antibody. This is clearly seen from the fact that a bottle-fed infant is inferior in resistance against infection than a breast-fed infant. The fact that the S-IgA given by lactation and passed through the stomach still retains its effectiveness as an immune antibody in the intestine shows that the S-IgA is not susceptible against proteases in the stomach and intestins and is stable under acidic conditions in the stomach. Some of the present inventors proved by an in vitro experiment that the S-IgA is far superior to the IgA in the resistance to acids and proteases [K. Uriu, Y. Uemura, S. Funakoshi, and T. Kano, the Physico-Chemical Biology, 18 (3), 214 (1974)]
The fact that the S-IgA given by the lactation retains its effectiveness in the intestinal tract of an infant shows that the S-IgA passed unchanged through the stomach and reached the intestinal tract. Because of the fact that the S-IgA secreted from the internal glands is present in the epithelial cells of mucous membrane, it might be considered that on arrival at the intestinal tract the S-IgA may be captured by the epithelial cells. However, since the antigen-antibody reaction proceeds comparatively rapidly and the lactation is carried out several times a day, it is quite understandable that the orally supplied S-IgA passes through the intestinal tract without being held by the epithelial cells, whereby the S-IgA acts effectively in attacking enteric-bacteria and entero-viruses.
It has been shown, on the other hand, that in the epithelial cells of mucous membrane there is also SC uncombined with IgA. The free SC is also present in an IgA-deficient patient. It is reported that when a large dose of blood plasma was administered to the IgA-deficient patient, IgA was found in the secretion of the patient [R. E. Petty, J. T. Cassidy, and D. B. Sullivan, Pediatrics, 51 (1), 44 (1973)]. Although it is presumed that this phenomenon is associated with the free SC present in the mucous membrane, the IgA in the blood stream is generally believed not to migrate into secretory organs or the migration, if any, is extremely low.
It is reported that in the IgA-deficient patient, the secretory organs secrete IgG and IgM to compensate the deficiency in IgA and the secreted IgG and IgM play the part of IgA [Proceedings of the Society for Experimental Biology and Medicine (Proceedings of Experimental Biology and Medicine)].
It is, of course, most desirable to feed an infant with the S-IgA which has been obtained from the secretion such as milk, saliva, etc. by way of concentrating and purifying treatments and made into a medical preparation or mixed with cow's milk (including processed milks). However, commercial production of such a medical preparation is extremely difficult in view of collecting raw materials.